Nizatidine, the systematic chemical name of which is N-[2-[[[2-(dimethylaminomethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2 -nitro-1,1-ethenediamine, and which has the formula (I): ##STR1## is known compound, effective as a histamine H2 receptor antagonist, and useful in the treatment of peptic ulcers. The compound and a method for its preparation are described in U.S. Pat. No. 4,375,547 Pioch, to Eli Lilly and Co.
A commercially attractive process for producing pharmaceuticals such as nizatidine should yield the product in a highly pure form, or at least in an easily purifiable form. This is particularly advantageous for the last step in a pharmaceutical product synthesis. If the recovery and purification of the product to the high standards required of a pharmaceutical are difficult and expensive to achieve, the process may not be economically viable.
The Bronsted basicity of nizatidine, i.e. its basicity towards protons, derives essentially from the dimethyl amino group on the thiazole ring acting in concert with the nitrogen of the thiazole ring. If, therefore, in the final synthetic step in making nizatidine there can be created a precursor which is much more weakly basic than nizatidine, then the separation of nizatidine from the precursor and other by-products derived from the precursor can be achieved by a simple acid-base extraction. This will constitute a rugged (in the sense of readily scaled-up, insensitive to parameter variable) but simple procedure for obtaining very pure pharmaceutical product which is industrially applicable.
In Canadian Patent 1,263,400 Alhede et al (Gea), there is disclosed a process for making ranitidine. Nizatidine is often compared with ranitidine, a compound having a similar pharmaceutical activity and chemical structure, differing Chemically from nizatidine, inter alia, in the presence of a furan ring system in place of the thiazole ring system of nizatidine. The Alhede et al synthesis of ranitidine involves as a final step replacement of a benzylic type hydroxyl by the dimethylamino function. Use of elevated temperatures and closed pressure vessels are reported to be required. There is no description of the benefits of this procedure for obtaining high quality product by simple extraction, nor that it might be applicable to any other product preparation besides ranitidine. Methods of chemical synthesis of ranitidine cannot predictably be applied to the synthesis of nizatidine, because of the differences in resonance and inductive effects introduced by the furan ring system as compared with the thiazole ring system.
It is an object of the present invention to provide a novel method for the synthesis of nizatidine.
It is a further object of the present invention to provide novel intermediates useful in such a synthesis.